1) Field of the Invention
This invention relates to new antibacterial 6-amido-1-methyl-2-(substituted-thio)-carbapenems and a process for their synthesis involving new azetidinone intermediates.
2) Brief Description of Disclosures in the Art
Carbapenem antibiotics, particularly imipenem (see U.S. Pat. Nos. 3,950,377 and 4,194,047) is well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections. ##STR1##
1-.beta.-Methylcarbapenems, as described in the reference Heterocycles, 1984, Vol. 21, pp. 29-40 by D. H. Shih, F. Baker, L. Cama and B. G. Christensen, are extremely useful and effective broad spectrum antibiotics, useful against a wide variety of bacteria including gram-positive bacteria such as S. aureus, Strep. sp., B. subtilis, and gram-negative bacteria such as E. coli, Shigella sp., Enterobacter sp., Klebsiella sp., Proteus, Serratia and Pseudomonas sp.
However, all of the above antibacterial carbapenems utilize 6-substituents other than amido or substituted amido which are the 6-substituents of choice in penicillin, e.g. ##STR2## or the cephalosporins, e.g. ##STR3##
6-Amidocarbapenems and penams are known in the art as exemplified in the following references: U.S. Pat. No. 4,260,627; U.S. Pat. No. 4,206,219; U.S. Pat. No. 4,217,453; U.S. Pat. No. 4,218,459; U.S. Pat. No. 4,218,463; U.S. Pat. No. 4,277,482; and U.S. Pat. No. 4,298,741 to Merck & Co., Inc. which describe 1-H-6-amidocarbapenems and 1-methyl-6-aminocarbapenems; BE 887,618 and U.S. Pat. No. 4,347,355 to Abbott which describe 1,1-diloweralkyl-6-amidocarbapenems; EPO Publication No. 040,494 and U.S. Pat. No. 4,348,264 to Pfizer which describes 1-hydroxy, acetoxy or 1,1-oxocarbapenems with 6-position conventional penicillin sidechains; EPO Publication Nos. 634,443 and 073,100 and U.S. Pat. No. 4,407,815 to Beecham which describe 1-H-6-amidocarbapenems and penams; Japanese Kokai 58 174 382 to Sanraku-Ocean Co. Ltd. which discloses 6-phthalimido-2-SR carbapenems; EPO Publication No. 045,198 to Takeda Chem. Ind. Ltd which discloses 1-alkyl-1-alkoxycarbonyl, cyano or COR-substituted-6-amidocarbapenems; and EPO Publication No. 116,854 to Hoffmann-LaRoche AG which discloses new azetidinone derivatives which can be used to prepare 1-H carbapenems; Sanraku EP 0,237,027 and Japanese Patent J6 3048-274A; and Bayer AG DE 3,509,769.
Literature articles relating to 1-H-6-amidocarbapenems discussing problems in ring closures and ester deblocking reactions include: Tetrahedron Letters, 1982, 23 (15), 1545-1548; Tetrahedron Letters, 1982, 23 (50), 5339-5342; L. C. Blaszczak, Eli Lilly Co. Report "Joint Great Lakes and Central Regional Meeting", Western Michigan University, May 23-24, 1984; J. Chem. Soc., Perkins Trans. I, 1982, 2123-2129; Helv. Chim. Acta, 1982, 65, 1378-1384; J.A.C.S., 1982, 104, 4262-4264; Chem. Pharm. Bull. 31 2578 (1983); N. Narisada et. al. 176th ACS National Meeting, Miami, Fla. 1978.; and Nouv. J. Chim. 7 691 (1983).
New antibacterial compounds are constantly being searched for to enhance the potency and decrease the side effects of current existing carbapenem antibiotics. Thus far, 1-methyl-6-amidocarbapenems have not been disclosed in the art.